15-43775541-C-T

Position:

• chr15-43775541-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_025165.3(ELL3):​c.553G>A​(p.Ala185Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000205 in 1,461,878 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: ELL3 NM_025165.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.873

Genes affected

ELL3 (HGNC:23113): (elongation factor for RNA polymerase II 3) Predicted to enable cis-regulatory region sequence-specific DNA binding activity. Involved in positive regulation of transcription, DNA-templated and transcription by RNA polymerase II. Located in several cellular components, including chromosome; cytosol; and nuclear lumen. Part of transcription elongation factor complex. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.22349572).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ELL3	NM_025165.3	c.553G>A	p.Ala185Thr	missense_variant	5/11	ENST00000319359.8	NP_079441.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ELL3	ENST00000319359.8	c.553G>A	p.Ala185Thr	missense_variant	5/11	1	NM_025165.3	ENSP00000320346	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000205 AC: 3 AN: 1461878 Hom.: 0 Cov.: 32 AF XY: 0.00000138 AC XY: 1 AN XY: 727242

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000270

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

May 20, 2024

The c.553G>A (p.A185T) alteration is located in exon 5 (coding exon 5) of the ELL3 gene. This alteration results from a G to A substitution at nucleotide position 553, causing the alanine (A) at amino acid position 185 to be replaced by a threonine (T). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.093
BayesDel_addAF	Benign	-0.16	T
BayesDel_noAF	Benign	-0.47
CADD	Benign	21
DANN	Uncertain	1.0
DEOGEN2	Benign	0.0027	T
Eigen	Uncertain	0.46
Eigen_PC	Uncertain	0.40
FATHMM_MKL	Benign	0.40	N
LIST_S2	Benign	0.69	T
M_CAP	Benign	0.010	T
MetaRNN	Benign	0.22	T
MetaSVM	Benign	-0.69	T
MutationAssessor	Uncertain	2.0	M
MutationTaster	Benign	0.88	D
PrimateAI	Benign	0.40	T
PROVEAN	Benign	-0.39	N
REVEL	Benign	0.14
Sift	Benign	0.13	T
Sift4G	Uncertain	0.060	T
Polyphen		0.99	D
Vest4		0.14
MutPred		0.42		Gain of helix (P = 0.0325);
MVP		0.42
MPC		0.20
ClinPred		0.74	D
GERP RS		4.8
Varity_R		0.098
gMVP		0.19

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.060		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr15-44067739;